Biomedical Engineering Reference
In-Depth Information
causes either exacerbation of mild PCP phenotypes in animals homozygotes
for mutations in other PCP genes or an appearance of full-fledged PCP de-
fects (inner ear, NT, heart) in otherwise normal heteroyzgotes bearing one
mutated allele of other PCP genes including
Vangl1
(
Antic et al., 2010; Song
et al., 2010; Torban et al., 2008
),
Dvl1/2/3
(
Etheridge et al., 2008; Wang,
Hamblet, et al., 2006
),
Fz1/2
(
Wang, Hamblet, et al., 2006; Yu et al., 2010
),
Celsr1
(
Curtin et al., 2003
),
Scribble
(
Murdoch et al., 2003
),
Ptk7
(
Lu et al.,
2004
), and
Sec24b
(
Merte et al., 2010
). These observations establish the
critical and dosage-sensitive functional role of Vangl2 in molecular
processes underlying PCP signaling in many cell types.
Mechanistically,
Lp
variants have been proposed to behave either as par-
tially penetrant with negative codominance or as haploid insufficiency in a
gene dosage-dependent pathway. In favor of the former are the observations
that (a) several Vangl2-associated PCP phenotypes appear more severe for
Lp
alleles (
Vangl2
D255E
,
Vangl2
S264N
) than for null allele (
Vangl2
TM/TM
)
(
Yin et al., 2012
); (b) Vangl1 and Vangl2 appear to physically interact
and, in cotransfection experiments,
Lp
alleles disrupt Vangl1/Vangl2 inter-
actions, as well as trafficking and membrane targeting of Vangl1 and Vangl2
(
Yin et al., 2012
), and decrease of the posttranslational modification of WT
protein (
Gao et al., 2011; Song et al., 2010
). In support of haploid
insufficiency in a gene dosage-dependent pathway are the observations
that (a) experimental overexpression or silencing of core PCP genes
causes the same phenotype in different animal models tested; (b) all
experimentally induced (
Gao et al., 2011; Song et al., 2010
) or naturally
occurring
Vangl2
mutations (
Guyot et al., 2011; Kibar, Underhill, et al.,
2001; Kibar, Vogan, et al., 2001
) described so far show varying degrees
of the same phenotype (looped tail, inner ear defects) in heterozygotes
and homozygotes
in vivo
; (c)
Lp
-associated Vangl2 protein variants are
expressed at lower levels
in vivo
(
Montcouquiol et al., 2006; Shafer,
Onishi, Lo, Colakoglu, & Zou, 2011; Torban et al., 2007
) and display
reduced stability and shorter half-life when tested
in vitro
(
Gravel et al.,
2010; Iliescu, Gravel, Horth, Kibar, et al., 2011
); (d) colocalization
studies by double immunofluorescence and confocal microscopy in
transfected MDCK cells show that expression of Vangl2
D255E
has no
effect on membrane targeting of WT Vangl2 (
Gravel et al., 2010
).
Finally, genetic background has a strong influence on penetrance and
expressivity of
Lp
-associated phenotypes (
Strong & Hollander, 1949
),
which complicates analysis of mode of inheritance of
Vangl2
mutations
and the associated interpretation of experimental results obtained
in vivo
.
